Objectives of the project are as follows: first to identify sexual dimorphisms and the role of gonadal steroids in the regulation of neural and glial signal transduction, proliferation, and survival and in the ontogeny of brain neurotransmitter systems; second, to resolve the mechanisms of both the acute (e.g. enhanced apoptosis) and subacute (e.g. altered neurotransmitter receptor message) neural effects of gonadal steroids; third, to determine the developmental-stage dependent neural consequences of gonadal steroids; and fourth, to identify the subsequent behavioral consequences of perinatal gonadal steroid manipulations. These objectives serve two overall goals: 1) Understanding neuroregulatory mechanisms of gonadal steroids of relevance for affective disorders; and 2) Defining the substrate of differential sensitivity, the process by which the same hormonal stimulus can elicit different responses in different subjects. Findings in the past year include the following: 1) Sexual Dimorphisms: new born male, but not female, rats respond to maternal deprivation with dramatic decreases in cortical NOS (nitric oxide synthase); embryonic cortical culture with estradiol for 72 hours produces explosive growth of MAP2 and 5HT-1A labeled neurons in cells from female, but not male, rats; 2) Mechanisms of Neuroprotection: estradiol increases phosphorylated Akt and blocks Abeta (31-35)-mediated cell death in hippocampal neurons. The neuroprotective effects of estradiol are reversed by co-culture with a PI3-kinase inhibitor, suggesting that activation of the protein kinase B pathway is one means by which estradiol may preserve neuronal integrity; 3) Non-genomic Mechanisms: the Slack (sequence like a calcium-activated potassium channel) type potassium channel appears in cortical neuronal membranes and is activated by estradiol through a non-traditional membrane ER binding site (not blocked by tamoxifen and present in cells that express Slack but not ER). These data suggest that gonadal steroids are significant regulators of cell survival and differentiation in the developing brain, where they undoubtedly play a major role in the formation of gonadal steroid sensitive circuitry. Further, these data complement our demonstrations of sexually dimorphic, gonadal steroid-dependent, neurotransmitter receptor modulation, effects which may underlie the ability of perinatal manipulations of gonadal steroids to alter subsequent behavior (sex and aggression) and neuroendocrine function (e.g. the capacity to express cyclic gonadotropin secretion). Finally, studies of estrogen and progesterone receptors have been undertaken in human post-mortem studies to help define possible relevant circuitry for the expression of gonadal steroid-regulated behaviors.